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Drug Discovery of DKK1 Inhibitors
Hewen Jiang1,2, Zongkang Zhang1,2, Yuanyuan Yu2,3,4
1School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China.
Abstract:
Dickkopf-1 (DKK1) is a well-characterized Wnt inhibitor and component of the Wnt/β-catenin signaling pathway, whose dysregulation is associated with multiple abnormal pathologies including osteoporosis, Alzheimer's disease, diabetes, and various cancers. The Wnt signaling pathway has fundamental roles in cell fate determination, cell proliferation, and survival; thus, its mis-regulation can lead to disease. Although DKK1 is involved in other signaling pathways, including the β-catenin-independent Wnt pathway and the DKK1/CKAP4 pathway, the inhibition of DKK1 to propagate Wnt/β-catenin signals has been validated as an effective way to treat related diseases. In fact, strategies for developing DKK1 inhibitors have produced encouraging clinical results in different pathological models, and many publications provide detailed information about these inhibitors, which include small molecules, antibodies, and nucleic acids, and may function at the protein or mRNA level. However, no systematic review has yet provided an overview of the various aspects of their development and prospects. Therefore, we review the DKK1 inhibitors currently available or under study and provide an outlook on future studies involving DKK1 and drug discovery.
Insights
Dickkopf-1 (DKK1) inhibitors show promise for treating diseases linked to Wnt/β-catenin pathway dysregulation. This review covers current DKK1 inhibitor development and future drug discovery prospects.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Dickkopf-1 (DKK1) is a key Wnt signaling pathway inhibitor implicated in diseases like osteoporosis, Alzheimer's, diabetes, and cancer.
- Dysregulation of the Wnt/β-catenin pathway, where DKK1 plays a role, is linked to various pathologies.
- While DKK1 interacts with other pathways, inhibiting DKK1 to restore Wnt/β-catenin signaling is a validated therapeutic strategy.
Purpose of the Study:
- To systematically review the development and prospects of Dickkopf-1 (DKK1) inhibitors.
- To provide an overview of current and emerging DKK1 inhibitor strategies for therapeutic applications.
Main Methods:
- Literature review of publications detailing DKK1 inhibitors.
- Analysis of different inhibitor types (small molecules, antibodies, nucleic acids) and their mechanisms of action (protein or mRNA level).
- Assessment of clinical results and pathological models involving DKK1 inhibition.
Main Results:
- Various DKK1 inhibitors, including small molecules, antibodies, and nucleic acids, have been developed.
- These inhibitors function at both protein and mRNA levels.
- Encouraging clinical results have been observed in different pathological models.
Conclusions:
- DKK1 inhibitors represent a promising therapeutic avenue for Wnt/β-catenin pathway-related diseases.
- Further research and development are needed to fully realize the potential of DKK1 inhibitors in drug discovery.
- This review offers an outlook on future studies involving DKK1 and therapeutic strategies.
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